19F: A Versatile Reporter for Non-Invasive Physiology and Pharmacology Using Magnetic Resonance

Abstract

The fluorine atom provides an exciting tool for diverse spectroscopic and imaging applications using Magnetic Resonance. The organic chemistry of fluorine is widely established and it can provide a stable moiety for interrogating many aspects of physiology and pharmacology in vivo. Strong NMR signal, minimal background signal and exquisite sensitivity to changes in the microenvironment have been exploited to design and apply diverse reporter molecules. Classes of agents are presented to investigate gene activity, pH, metal ion concentrations (e.g., Ca(2+), Mg(2+), Na(+)), oxygen tension, hypoxia, vascular flow and vascular volume. In addition to interrogating speciality reporter molecules, (19)F NMR may be used to trace the fate of fluorinated drugs, such as chemotherapeutics (e.g., 5-fluorouracil, gemcitabine), anesthetics (e.g., isoflurane, methoxyflurane) and neuroleptics. NMR can provide useful information through multiple parameters, including chemical shift, scalar coupling, chemical exchange and relaxation processes (R1 and R2). Indeed, the large chemical shift range (approximately 300 ppm) can allow multiple agents to be examined, simultaneously, using NMR spectroscopy or chemical shift selective imaging.

Gd‐enhanced MR images of substrates other than water

“…These procedures are often indicated as spectroscopic imaging and refer to endogenous substrates like lactate, choline, creatine, etc. (4-6), although images of exogenous substrates (mainly 19 F-containing molecules) have also been reported (7)(8)(9).…”

Structural basis for the enhanced stability of highly fluorinated proteins

“…The introduction of fluorinated amino acids into proteins has attracted particular interest, because although essentially absent from biology, fluorine has proved a remarkably useful element to probe the workings of biological molecules. For example, fluorinated substrates have been extensively used to investigate enzyme mechanisms, and 19 F NMR has proved a valuable tool for studying structure, dynamics, and interactions of fluorine-labeled proteins, peptides, lipids, and nucleic acids (4)(5)(6)(7)(8)(9). Fluorinated molecules also have important medical applications, exemplified by 20% of all pharmaceuticals containing fluorine, which improves pharmacokinetic properties (10).…”

Effective Kinetic Methods and Tools in Investigating the Mechanism of Action of Specific Hydrolases

“…On the other hand, the 19 F has many favorable NMR characteristics, including a nuclear spin I = 1/2, 100% natural abundance, high sensitivity and large chemical shift range (500 ppm) (Battiste & Newmark, 2006). Endogenous fluorine has a very short T 2 relaxation time and the resulting signal is below the limits of NMR detection in most biological systems of interest (Yu et al, 2005). The 15 N Nitrogen nuclei are frequently located at the interaction sites of biomolecules; for example, amide nitrogens in peptides are the key in maintaining the peptide backbone conformation by hydrogen bonding.…”